ProjectSummary/Abstract Alzheimer?sDisease(AD)andrelateddementiasarethemostcommoncauseofageing- dependentdementiaintheworldandisassociatedwithcerebralamyloidplaquesandneurofibrillary tangles(NFTs).CurrentdrugdiscoveryapproachesinADandrelateddementiashavefocusedon preventingformationorremovingexistingamyloiddeposits.However,theseapproacheshavesofar failedandthemostadvancedalternativehypothesisisthatoftautoxicity.Ourpreliminarydataindicate thattaualsomediatesbehavioraldeficitsinFamilialDanishDementia,anAD-likedementiaassociated withmutationsintheregulatorofAPPprocessingBRI2/ITM2B,alsocharacterizedbytauopathy.Some evidencesuggeststhatcaspasesareactivatedearlyintheprogressionofADandmayplayarolein neuronallossandNFTpathology.TauiscleavedatD421byexecutionercaspasestogenerate?Tau. Dataintheliteraturesuggestthat?TaufacilitatesNFTformationandcanexerttoxiceffects.InAD brains?TauassociateswithNFTsandcorrelateswithcognitivedecline.Thesefindingshaveleadtothe hypothesisthat?Tauisacriticaltoxicmoietyunderlyingneurodegeneration.However,the publisheddataarealsocompatiblewiththehypothesisthatcleavageoftaubycaspasecould representanegativefeed-backmechanismaimedtoeliminateatoxicformoftau.Todirectlytest thesepossibilities,wehavegeneratedknock-inmiceinwhichtheendogenoustaucodonGACinexon 12,encodingforD421,hasbeenmutatedintoAAC,whichnowencodesforanAsparagine(N).These knock-inmice,calledTauDNexpressataumutant,cannotbecleavedbycaspasesandthereforecannot generate?Tau.TauDNmicewillbeusedtodeterminewhether?Taumediatessynapticplasticityand memorydeficitsinanimalmodelsofFDDandtherelatedFamilialBritishDementia(FBD),two neurodegenerativedisordersinwhichtauplaysapathogenicrole.Ourstudieswillspeaktowhether modulationof?TauformationisapotentialstrategyforthetreatmentofADandother neurodegenerativedisordersmediatedbyneuro-toxictauforms.